Alcohol abuse is a leading cause of morbidity and mortality worldwide. Estimates suggest that in the US 18 million Americans abuse alcohol and that alcoholic liver disease (ALD) affects over 10 million people. Alcohol abuse's deleterious effects on the liver leads to pathologically distinct entities: steatosis, steatohepatitis (ASH), fibrosis and cirrhosis. Fatty liver occurs in up to 90% of alcoholics, but only a subset of heavy drinkers progress to more severe injury. While genetic and environmental risk factors can accelerate progression of ALD in individual heavy drinkers, specific genetic polymorphisms predicting risk for ALD are not well defined. Enhanced inflammation in the liver during ethanol exposure is an important contributor to ALD. Using a pre- clinical mouse model of chronic ethanol exposure, we have identified macrophage migration inhibitory factor (MIF) as an important contributor to ethanol-induced steatosis and inflammation. MIF is a pleiotropic cytokine that enhances the activation of macrophages by increasing inflammatory cytokine production and suppressing activation-induced apoptosis. MIF also counter-regulates the immunosuppressive and anti-inflammatory activities of glucocorticoids. Analysis of the human MIF gene has identified important functional polymorphisms in the promoter region, including a biallelic, CATT(5-8) tetranucleotide repeat at position -794 and a G/C single-nucleotide polymorphism (SNP) at position -173 in the 5'promoter region of MIF. Higher CATT repeats increase MIF expression and are associated with the incidence or severity of a number of inflammatory diseases, including rheumatoid arthritis, inflammatory bowel disease and asthma. Here we propose an international collaboration to characterize the role of MIF in ALD. The mechanisms of MIF action in ethanol-induced liver injury will be investigated in pre-clinical mouse models of steatosis and ASH. These data will then be used to move from bench to bedside and determine if genetic variation in MIF expression in human populations predicts the incidence and/or severity of ALD. Further, we will determine whether polymorphisms in the MIF promoter predict the sensitivity of patients to glucocorticoid therapy in ASH. We will generate a unique biobank of DNA samples from: 1) subjects who were identified as heavy drinkers in the DIONYSOS study, which sampled the entire population of two villages in Italy and 2) patients spanning the natural history of ALD, from steatosis to fibrosis and hepatocarcinoma, as well as those with severe ASH, from Barcelona, Spain. Studies in patients with severe ASH will be confirmed in a US cohort of patients in Cleveland Ohio. This international collaboration thus takes a highly innovative, translational approach to investigate mechanisms and therapies for ALD. Results from these studies will facilitate the development of a personalized medicine approach to the treatment of ALD, which could allow clinicians to dissect the prevailing pathophysiological mechanisms in an individual patient and adapt therapeutic strategies accordingly. Further, this project will result in the development of a unique and highly informative set of linked genetic and clinical data that can be shared with investigators nationall and internationally for testing specific hypotheses related to the development and treatment of ALD. PUBLIC HEALTH RELEVANCE: Alcohol abuse is a leading cause of morbidity and mortality worldwide and recent data indicate that alcoholic liver disease affects over 10 million Americans. The long-term goals of this research project are to make use of pre-clinical mouse models of ethanol-induced liver injury to discover the pathophysiological role of macrophage migration inhibitory factor (MIF) in un-controlled inflammation in the liver after ethanol exposure By building an international collaboration with investigators in Europe, we will make use of novel DNA samples from unique subject/patient cohorts from Italy and Spain to determine whether genetic polymorphisms in MIF contribute to the incidence and/or severity of ALD in heavy drinkers.